Our goal is to understand the cellular and molecular mechanism by which prenatal and neonatal DES exposure permanently alters uterine cell growth and differentiation. Our approach has been to investigate the role of both positive and negative growth factors in estrogen-induced proliferation of normal mouse uterus. A role of positive acting polypeptide growth factors is suggested by analysis of mouse uterine luminal fluid which demonstrates that high levels of insulin-like growth factor-1 (IGF-1), epidermal growth factor-like peptides (EGF), and lactoferrin are secreted upon estrogen stimulation. Evidence that these factors may act as positive mediators of estrogen-induced growth has been obtained from in vitro studies of mouse uterine cell or organ cultures and from in vivo studies of transplanted pellets containing IGF-1 or EGF under the kidney capsule. In addition to the induction of growth stimulatory factors, estrogen treatment also modified uterine cell response to a growth inhibitor, transforming growth factor-beta. Preliminary studies suggest that prenatal or neonatal DES exposure result in a modification of uterine receptors for these growth regulatory factors; such receptor alterations may contribute to the teratogenic and carcinogenic effects of DES. Although our understanding of estrogen action is not clear, estrogen appears to enhance uterine cell proliferation, not only, by inducing multiple growth factors that act in concert to stimulate cell cycle progression, but also, by altering the response of uterine cells to growth inhibitory signals which may amplify the proliferative potential of the cells. Our future plans are to continue to characterize and define the role of peptide mediators of estrogen-induced growth, determine the cell type responsible for the synthesis of these factors, locate the cellular target where these factors act, elucidate whether these factors act alone, synergistically or temporally, control growth, and further define the role of growth inhibitors in modulating uterine cell proliferative response.